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Cells
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Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking
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Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 11267

Special Issue Editors

Prof. Dr. Tracy Handel

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Guest Editor
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA
Dr. Christopher Schafer

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Guest Editor
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
Dr. Siyi (May) Gu

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Guest Editor
Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA

Special Issue Information

Dear colleagues,

Chemokine receptors (CKRs) are a family of G protein-coupled receptors (GPCRs) that express mostly on the surface of immune cells. With about 20 distinct receptors in 4 major subfamilies (CC, CXC, XC, CX), the receptors interact with over 40 different chemokine ligands to orchestrate cell migration during immune surveillance and inflammation. Chemokine signaling is incredibly complex: structurally dynamic CKRs often interact with multiple chemokines and couple multiple transducers, resulting in diverse activatison cues that are essential for the recruitment and positioning of immune cells at the right time and place. In addition to normal physiological processes, they also play important roles in many diseases such as cancer, HIV, and neurological disorders. In order to precisely determine their role in health, disease, and their potential as therapeutic targets, it is critical to understand the mechanisms that govern CKR interaction plasticity with different chemokines and transducers, and how this leads to different signaling and trafficking outcomes. In this Special Issue of Cells, we will gather articles, reviews, and opinion pieces on: 1) structural mechanisms of chemokine–receptor–transducer interactions; 2) molecular mechanisms of CKR signaling, subcellular trafficking and recycling; 3) signaling bias; and 4) methods for studying chemokine receptor structure and signaling.

Prof. Dr. Tracy Handel
Dr. Christopher Schafer
Dr. Siyi (May) Gu
Guest Editors

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Keywords

  • chemokine receptors
  • GPCR
  • structural mechanism
  • signaling
  • trafficking
  • recycling

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Published Papers (4 papers)

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Research

19 pages, 3450 KiB  
Article
The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis
by Kathryn E. Luker and Gary D. Luker
Cells 2022, 11(11), 1775; https://doi.org/10.3390/cells11111775 - 28 May 2022
Cited by 2 | Viewed by 3161
Abstract
In response to CXCL12, CXCR4 and ACKR3 both recruit β-arrestin 2, regulating the assembly of interacting proteins that drive signaling and contribute to the functions of both receptors in cancer and multiple other diseases. A prior proteomics study revealed that β-arrestin 2 scaffolds [...] Read more.
In response to CXCL12, CXCR4 and ACKR3 both recruit β-arrestin 2, regulating the assembly of interacting proteins that drive signaling and contribute to the functions of both receptors in cancer and multiple other diseases. A prior proteomics study revealed that β-arrestin 2 scaffolds pyruvate kinase M2 (PKM2), an enzyme implicated in shifting cells to glycolytic metabolism and poor prognosis in cancer. We hypothesized that CXCL12 signaling regulates PKM2 protein interactions, oligomerization, and glucose metabolism. We used luciferase complementation in cell-based assays and a tumor xenograft model of breast cancer in NSG mice to quantify how CXCR4 and ACKR3 change protein interactions in the β-arrestin-ERK-PKM2 pathway. We also used mass spectrometry to analyze the effects of CXCL12 on glucose metabolism. CXCL12 signaling through CXCR4 and ACKR3 stimulated protein interactions among β-arrestin 2, PKM2, ERK2, and each receptor, leading to the dissociation of PKM2 from β-arrestin 2. The activation of both receptors reduced the oligomerization of PKM2, reflecting a shift from tetramers to dimers or monomers with low enzymatic activity. Mass spectrometry with isotopically labeled glucose showed that CXCL12 signaling increased intermediate metabolites in glycolysis and the pentose phosphate pathway, with ACKR3 mediating greater effects. These data establish how CXCL12 signaling regulates PKM2 and reprograms cellular metabolism. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking)
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14 pages, 2837 KiB  
Article
Shifting CCR7 towards Its Monomeric Form Augments CCL19 Binding and Uptake
by Oliver J. Gerken, Marc Artinger and Daniel F. Legler
Cells 2022, 11(9), 1444; https://doi.org/10.3390/cells11091444 - 25 Apr 2022
Cited by 5 | Viewed by 2418
Abstract
The chemokine receptor CCR7, together with its ligands, is responsible for the migration and positioning of adaptive immune cells, and hence critical for launching adaptive immune responses. CCR7 is also induced on certain cancer cells and contributes to metastasis formation. Thus, CCR7 expression [...] Read more.
The chemokine receptor CCR7, together with its ligands, is responsible for the migration and positioning of adaptive immune cells, and hence critical for launching adaptive immune responses. CCR7 is also induced on certain cancer cells and contributes to metastasis formation. Thus, CCR7 expression and signalling must be tightly regulated for proper function. CCR7, like many other members of the G-protein coupled receptor superfamily, can form homodimers and oligomers. Notably, danger signals associated with pathogen encounter promote oligomerisation of CCR7 and is considered as one layer of regulating its function. Here, we assessed the dimerisation of human CCR7 and several single point mutations using split-luciferase complementation assays. We demonstrate that dimerisation-defective CCR7 mutants can be transported to the cell surface and elicit normal chemokine-driven G-protein activation. By contrast, we discovered that CCR7 mutants whose expression are shifted towards monomers significantly augment their capacities to bind and internalise fluorescently labelled CCL19. Modeling of the receptor suggests that dimerisation-defective CCR7 mutants render the extracellular loops more flexible and less structured, such that the chemokine recognition site located in the binding pocket might become more accessible to its ligand. Overall, we provide new insights into how the dimerisation state of CCR7 affects CCL19 binding and receptor trafficking. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking)
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Graphical abstract

15 pages, 1898 KiB  
Article
A Scintillation Proximity Assay for Real-Time Kinetic Analysis of Chemokine–Chemokine Receptor Interactions
by Stefanie Alexandra Eberle and Martin Gustavsson
Cells 2022, 11(8), 1317; https://doi.org/10.3390/cells11081317 - 13 Apr 2022
Cited by 1 | Viewed by 2720
Abstract
Chemokine receptors are extensively involved in a broad range of physiological and pathological processes, making them attractive drug targets. However, despite considerable efforts, there are very few approved drugs targeting this class of seven transmembrane domain receptors to date. In recent years, the [...] Read more.
Chemokine receptors are extensively involved in a broad range of physiological and pathological processes, making them attractive drug targets. However, despite considerable efforts, there are very few approved drugs targeting this class of seven transmembrane domain receptors to date. In recent years, the importance of including binding kinetics in drug discovery campaigns was emphasized. Therefore, kinetic insight into chemokine–chemokine receptor interactions could help to address this issue. Moreover, it could additionally deepen our understanding of the selectivity and promiscuity of the chemokine–chemokine receptor network. Here, we describe the application, optimization and validation of a homogenous Scintillation Proximity Assay (SPA) for real-time kinetic profiling of chemokine–chemokine receptor interactions on the example of ACKR3 and CXCL12. The principle of the SPA is the detection of radioligand binding to receptors reconstituted into nanodiscs by scintillation light. No receptor modifications are required. The nanodiscs provide a native-like environment for receptors and allow for full control over bilayer composition and size. The continuous assay format enables the monitoring of binding reactions in real-time, and directly accounts for non-specific binding and potential artefacts. Minor adaptations additionally facilitate the determination of equilibrium binding metrics, making the assay a versatile tool for the study of receptor–ligand interactions. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking)
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15 pages, 5474 KiB  
Article
The Atypical Chemerin Receptor GPR1 Displays Different Modes of Interaction with β-Arrestins in Humans and Mice with Important Consequences on Subcellular Localization and Trafficking
by Gaetan-Nagim Degroot, Valentin Lepage, Marc Parmentier and Jean-Yves Springael
Cells 2022, 11(6), 1037; https://doi.org/10.3390/cells11061037 - 18 Mar 2022
Cited by 7 | Viewed by 2236
Abstract
Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, [...] Read more.
Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, it is unknown whether mouse and human ACKRs share the same properties. In this study, we compared the properties of the human and mouse atypical chemerin receptor GPR1 and showed that they behave differently regarding their interaction with β-arrestins. Human hGPR1 interacts with β-arrestins as a result of chemerin stimulation, whereas its mouse orthologue mGPR1 displays a strong constitutive interaction with β-arrestins in basal conditions. The constitutive interaction of mGPR1 with β-arrestins is accompanied by a redistribution of the receptor from the plasma membrane to early and recycling endosomes. In addition, β-arrestins appear mandatory for the chemerin-induced internalization of mGPR1, whereas they are dispensable for the trafficking of hGPR1. However, mGPR1 scavenges chemerin and activates MAP kinases ERK1/2 similarly to hGPR1. Finally, we showed that the constitutive interaction of mGPR1 with β-arrestins required different structural constituents, including the receptor C-terminus and arginine 3.50 in the second intracellular loop. Altogether, our results show that sequence variations within cytosolic regions of GPR1 orthologues influence their ability to interact with β-arrestins, with important consequences on GPR1 subcellular distribution and trafficking. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Chemokine Receptor Signaling and Trafficking)
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